Wang Jiayin, Lin Yan, Xu Zhihong, Yan Chuanzhu, Zhao Yuying, Ji Kunqian
Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, 266035, Shandong, China.
Cerebellum. 2024 Oct;23(5):1824-1838. doi: 10.1007/s12311-024-01671-4. Epub 2024 Mar 2.
COQ8A plays an important role in the biosynthesis of coenzyme Q10 (CoQ10), and variations in COQ8A gene are associated with primary CoQ10 deficiency-4 (COQ10D4), also known as COQ8A-ataxia. The current understanding of the association between the specific variant type, the severity of CoQ10 deficiency, and the degree of oxidative stress in individuals with primary CoQ10 deficiencies remains uncertain. Here we provide a comprehensive analysis of the clinical and genetic characteristics of an 18-year-old patient with COQ8A-ataxia, who exhibited novel compound heterozygous variants (c.1904_1906del and c.637C > T) in the COQ8A gene. These variants reduced the expression levels of COQ8A and mitochondrial proteins in the patient's muscle and skin fibroblast samples, contributed to mitochondrial respiration deficiency, increased ROS production and altered mitochondrial membrane potential. It is worth noting that the optimal treatment for COQ8A-ataxia remains uncertain. Presently, therapy consists of CoQ10 supplementation, however, it did not yield significant improvement in our patient's symptoms. Additionally, we reviewed the response of CoQ10 supplementation and evolution of patients in previous literatures in detail. We found that only half of patients could got notable improvement in ataxia. This research aims to expand the genotype-phenotype spectrum of COQ10D4, address discrepancies in previous reviews regarding the effectiveness of CoQ10 in these disorders, and help to establish a standardized treatment protocol for COQ8A-ataxia.
COQ8A在辅酶Q10（CoQ10）的生物合成中起重要作用，COQ8A基因的变异与原发性辅酶Q10缺乏症4型（COQ10D4）相关，也称为COQ8A共济失调。目前，对于原发性辅酶Q10缺乏症患者中特定变异类型、辅酶Q10缺乏的严重程度以及氧化应激程度之间的关联尚不确定。在此，我们对一名18岁的COQ8A共济失调患者的临床和遗传特征进行了全面分析，该患者在COQ8A基因中表现出新型复合杂合变异（c.1904_1906del和c.637C>T）。这些变异降低了患者肌肉和皮肤成纤维细胞样本中COQ8A和线粒体蛋白的表达水平，导致线粒体呼吸功能缺陷，增加活性氧生成并改变线粒体膜电位。值得注意的是，COQ8A共济失调的最佳治疗方法仍不确定。目前，治疗方法包括补充辅酶Q10，然而，这并未使我们患者的症状得到显著改善。此外，我们详细回顾了先前文献中补充辅酶Q10的反应及患者的病情演变。我们发现只有一半的患者共济失调症状能得到显著改善。本研究旨在扩展COQ10D4的基因型-表型谱，解决先前综述中关于辅酶Q10在这些疾病中有效性的差异，并有助于建立COQ8A共济失调的标准化治疗方案。
